Showing papers by "Paris Descartes University published in 2009"
TL;DR: It is argued that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
Abstract: Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
4,369 citations
TL;DR: The size of the corpus, the language register on which the corpus is based, and the definition of the frequency measure were investigated, finding that lemma frequencies are not superior to word form frequencies in English and that a measure of contextual diversity is better than a measure based on raw frequency of occurrence.
Abstract: Word frequency is the most important variable in research on word processing and memory. Yet, the main criterion for selecting word frequency norms has been the availability of the measure, rather than its quality. As a result, much research is still based on the old Kucera and Francis frequency norms. By using the lexical decision times of recently published megastudies, we show how bad this measure is and what must be done to improve it. In particular, we investigated the size of the corpus, the language register on which the corpus is based, and the definition of the frequency measure. We observed that corpus size is of practical importance for small sizes (depending on the frequency of the word), but not for sizes above 16–30 million words. As for the language register, we found that frequencies based on television and film subtitles are better than frequencies based on written sources, certainly for the monosyllabic and bisyllabic words used in psycholinguistic research. Finally, we found that lemma frequencies are not superior to word form frequencies in English and that a measure of contextual diversity is better than a measure based on raw frequency of occurrence. Part of the superiority of the latter is due to the words that are frequently used as names. Assembling a new frequency norm on the basis of these considerations turned out to predict word processing times much better than did the existing norms (including Kucera & Francis and Celex). The new SUBTL frequency norms from the SUBTLEXUS corpus are freely available for research purposes from http://brm.psychonomic-journals.org/content/supplemental, as well as from the University of Ghent and Lexique Web sites.
2,106 citations
TL;DR: It is shown that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1 β (IL-1β).
Abstract: The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.
1,628 citations
TL;DR: Functional characterization of monocytes is in progress in humans and rodents and will provide a better understanding of the pathophysiology of inflammation.
Abstract: Monocytes are circulating blood leukocytes that play important roles in the inflammatory response, which is essential for the innate response to pathogens. But inflammation and monocytes are also involved in the pathogenesis of inflammatory diseases, including atherosclerosis. In adult mice, monocytes originate in the bone marrow in a Csf-1R (MCSF-R, CD115)-dependent manner from a hematopoietic precursor common for monocytes and several subsets of macrophages and dendritic cells (DCs). Monocyte heterogeneity has long been recognized, but in recent years investigators have identified three functional subsets of human monocytes and two subsets of mouse monocytes that exert specific roles in homeostasis and inflammation in vivo, reminiscent of those of the previously described classically and alternatively activated macrophages. Functional characterization of monocytes is in progress in humans and rodents and will provide a better understanding of the pathophysiology of inflammation.
1,559 citations
TL;DR: Systematic analysis of gnotobiotic mice indicated that colonization by a whole mouse microbiota orchestrated a broad spectrum of proinflammatory T helper 1 (Th1), Th17, and regulatory T cell responses whereas most tested complex microbiota and individual bacteria failed to efficiently stimulate intestinal Tcell responses.
1,307 citations
TL;DR: Recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-κB in human cancer, particularly in multiple myeloma are discussed.
Abstract: The nuclear factor κB (NF-κB) signalling pathway has been implicated in cancer development and progression, as well as in resistance to chemotherapy and radiation therapy. In this Perspective, Baud and Karin explore the therapeutic potential of targeting NF-κB in cancer, and discuss the challenges posed by this approach. Nuclear factor κB (NF-κB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-κB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-κB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-κB in cancer, and the possible complications and pitfalls of such an approach, are explored.
948 citations
TL;DR: CABG might be a better option for patients with diabetes and patients aged 65 years or older because it is found mortality to be lower in these subgroups, so choice of treatment should depend on patient preferences for other outcomes.
710 citations
TL;DR: It is shown that the surface layer on the dormant conidia masks their recognition by the immune system and hence prevents immune response, and also immunologically silences airborne moulds.
Abstract: The air we breathe is filled with thousands of fungal spores (conidia) per cubic metre, which in certain composting environments can easily exceed 10(9) per cubic metre. They originate from more than a hundred fungal species belonging mainly to the genera Cladosporium, Penicillium, Alternaria and Aspergillus. Although these conidia contain many antigens and allergens, it is not known why airborne fungal microflora do not activate the host innate immune cells continuously and do not induce detrimental inflammatory responses following their inhalation. Here we show that the surface layer on the dormant conidia masks their recognition by the immune system and hence prevents immune response. To explore this, we used several fungal members of the airborne microflora, including the human opportunistic fungal pathogen Aspergillus fumigatus, in in vitro assays with dendritic cells and alveolar macrophages and in in vivo murine experiments. In A. fumigatus, this surface 'rodlet layer' is composed of hydrophobic RodA protein covalently bound to the conidial cell wall through glycosylphosphatidylinositol-remnants. RodA extracted from conidia of A. fumigatus was immunologically inert and did not induce dendritic cell or alveolar macrophage maturation and activation, and failed to activate helper T-cell immune responses in vivo. The removal of this surface 'rodlet/hydrophobin layer' either chemically (using hydrofluoric acid), genetically (DeltarodA mutant) or biologically (germination) resulted in conidial morphotypes inducing immune activation. All these observations show that the hydrophobic rodlet layer on the conidial cell surface immunologically silences airborne moulds.
686 citations
TL;DR: Depletion of PERK, caspase‐8 or SNAREs had no effect on cell death induced by anthracyclines, yet abolished the immunogenicity of cell death, which could be restored by absorbing recombinant CRT to the cell surface.
Abstract: Dying tumour cells can elicit a potent anticancer immune response by exposing the calreticulin (CRT)/ERp57 complex on the cell surface before the cells manifest any signs of apoptosis. Here, we enumerate elements of the pathway that mediates pre-apoptotic CRT/ERp57 exposure in response to several immunogenic anticancer agents. Early activation of the endoplasmic reticulum (ER)-sessile kinase PERK leads to phosphorylation of the translation initiation factor eIF2α, followed by partial activation of caspase-8 (but not caspase-3), caspase-8-mediated cleavage of the ER protein BAP31 and conformational activation of Bax and Bak. Finally, a pool of CRT that has transited the Golgi apparatus is secreted by SNARE-dependent exocytosis. Knock-in mutation of eIF2α (to make it non-phosphorylatable) or BAP31 (to render it uncleavable), depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs abolished CRT/ERp57 exposure induced by anthracyclines, oxaliplatin and ultraviolet C light. Depletion of PERK, caspase-8 or SNAREs had no effect on cell death induced by anthracyclines, yet abolished the immunogenicity of cell death, which could be restored by absorbing recombinant CRT to the cell surface.
682 citations
Johns Hopkins University1, Paris Descartes University2, University of Barcelona3, University of Colorado Denver4, University of Pennsylvania5, University of Chicago6, University of Alberta Hospital7, University of Cambridge8, Vanderbilt University Medical Center9, Stanford University10, University of Giessen11, Virginia Commonwealth University12, University of California, San Diego13, University of Paris-Sud14
TL;DR: An overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins is provided, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy.
646 citations
TL;DR: The Das28 (CRP) has been validated against radiographic progression and physical function and the validation profile was similar to the DAS28 (ESR), indicating that both measures are useful for assessing disease activity in patients with rheumatoid arthritis.
Abstract: Objective: To validate and compare the definition of the Disease Activity Score 28 based on C-reactive protein (DAS28 (CRP)) to the definition based on erythrocyte sedimentation rate (ESR). Methods: Data were analysed from two randomised, double-blind, placebo-controlled trials of abatacept of 6-month and 12-month duration in patients with rheumatoid arthritis. European League Against Rheumatism (EULAR) response criteria and the proportion of patients in remission (DAS28 Results: There was general agreement in determining the EULAR responder state using both DAS28 definitions (κ = 0.80, 95% CI 0.76 to 0.83). Overall, there was 82.4% agreement on the EULAR response criteria; when disagreements occurred, the DAS28 (CRP) yielded a better EULAR response more often then DAS28 (ESR) (12.6% vs 4.9%, respectively). There was also agreement in determining remission: κ = 0.69 (95% CI 0.60 to 0.78). Radiographic progression decreased in patients treated with abatacept across EULAR states (from none to moderate to good) based on both definitions. For patients treated with placebo, the trend was not as pronounced, with radiographic scores higher for moderate vs non-responders. For physical function, similar trends were observed across the EULAR states for both DAS28 definitions. Conclusions: The DAS28 (CRP) has been validated against radiographic progression and physical function. While the DAS28 (CRP) yielded a better EULAR response more often than the DAS28 (ESR), the validation profile was similar to the DAS28 (ESR), indicating that both measures are useful for assessing disease activity in patients with rheumatoid arthritis.
TL;DR: This review will focus on the implication of brain endothelial tight junctions in BBB architecture and physiology, will discuss the consequences of BBB dysfunction in these CNS diseases and will present some therapeutic strategies for drug delivery to the brain across the BBB.
TL;DR: A systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA) was performed in Medline, Cochrane and EMBASE as mentioned in this paper.
Abstract: Objective: To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA). Methods: A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied. Results: 88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a–2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b–4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b–4). Conclusion: This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.
TL;DR: The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy, and the increased risk with early anti-tumor necrosis factor treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.
Abstract: Background
Tuberculosis (TB) is associated with anti-tumour necrosis factor (TNF) therapy but whether it is drug-specific remains a concern. Our objective was to describe cases of tuberculosis associated with anti-TNF therapy, identify risk factors and estimate the incidence.
Johns Hopkins University1, Maastricht University2, University of Western Australia3, Stanford University4, University of Rennes5, Paris Descartes University6, University of Auvergne7, French Institute of Health and Medical Research8, McGill University9, Saint Louis University10, University of Manchester11
TL;DR: The focus of the task force work reported here is to develop criteria for apathy that will be widely accepted, have clear operational steps, and be easily applied in practice and research settings.
TL;DR: The accumulated evidence demonstrates that microsaccades serve both perceptual and oculomotor goals and although in some cases their contribution is neither necessary nor unique, micros Accades are a malleable tool conveniently employed by the visual system.
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TL;DR: “Brian” is a simulator for spiking neural networks that uses vector-based computation to allow for efficient simulations, and is particularly useful for neuroscientific modelling at the systems level, and for teaching computational neuroscience.
Abstract: "Brian" is a simulator for spiking neural networks (http://www.briansimulator.org). The focus is on making the writing of simulation code as quick and easy as possible for the user, and on flexibility: new and non-standard models are no more difficult to define than standard ones. This allows scientists to spend more time on the details of their models, and less on their implementation. Neuron models are defined by writing differential equations in standard mathematical notation, facilitating scientific communication. Brian is written in the Python programming language, and uses vector-based computation to allow for efficient simulations. It is particularly useful for neuroscientific modelling at the systems level, and for teaching computational neuroscience.
Erasmus University Rotterdam1, Paris Descartes University2, National Institutes of Health3, University of Oxford4, University of Florence5, Leiden University Medical Center6, University of Giessen7, Radboud University Nijmegen8, Maastricht University9, University of Birmingham10, University of Paris11, University of Antwerp12, Dresden University of Technology13
TL;DR: Phaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure and SDHB immunohistsochemistry could improve the diagnosis, according to a large retrospective and prospective tumour series.
Abstract: BACKGROUND: Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. METHODS: Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. FINDINGS: SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively. INTERPRETATION: Phaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma-paraganglioma syndrome. FUNDING: The Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Sante et de la Recherche Medicale, and a PHRC grant COMETE 3 for the COMETE network.
TL;DR: Three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition have a homozygous nonsense mutation in STIM1 that abrogates expression ofSTIM1 and Ca(2+) influx.
Abstract: A mutation in ORAI1, the gene encoding the pore-forming subunit of the Ca(2+)-release-activated Ca(2+) (CRAC) channel, abrogates the store-operated entry of Ca(2+) into cells and impairs lymphocyte activation. Stromal interaction molecule 1 (STIM1) in the endoplasmic reticulum activates ORAI1-CRAC channels. We report on three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition. Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx.
TL;DR: It is found that Hif-1alpha was not necessary for iron absorption, whereas HIF-2alpha played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the gene encoding divalent metal transporter 1 (DMT1), the principal intestinal iron transporter.
Abstract: HIF transcription factors (HIF-1 and HIF-2) are central mediators of cellular adaptation to hypoxia. Because the resting partial pressure of oxygen is low in the intestinal lumen, epithelial cells are believed to be mildly hypoxic. Having recently established a link between HIF and the iron-regulatory hormone hepcidin, we hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical roles in regulating intestinal iron absorption. To explore this idea, we first established that the mouse duodenum, the site of iron absorption in the intestine, is hypoxic and generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium. Using these mice, we found that HIF-1alpha was not necessary for iron absorption, whereas HIF-2alpha played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the gene encoding divalent metal transporter 1 (DMT1), the principal intestinal iron transporter. Specific deletion of Hif2a led to a decrease in serum and liver iron levels and a marked decrease in liver hepcidin expression, indicating the involvement of an induced systemic response to counteract the iron deficiency. This finding may provide a basis for the development of new strategies, specifically in targeting HIF-2alpha, to improve iron homeostasis in patients with iron disorders.
TL;DR: Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment and prevention subgroups at 12 months.
TL;DR: The identification of AMPK targets in hepatic metabolism should be useful in developing treatments to reverse metabolic abnormalities of type 2 diabetes and the metabolic syndrome.
Abstract: As the liver is central in the maintenance of glucose homeostasis and energy storage, knowledge of the physiology as well as physiopathology of hepatic energy metabolism is a prerequisite to our understanding of whole-body metabolism. Hepatic fuel metabolism changes considerably depending on physiological circumstances (fed vs. fasted state). In consequence, hepatic carbohydrate, lipid and protein synthesis/utilization are tightly regulated according to needs. Fatty liver and hepatic insulin resistance (both frequently associated with the metabolic syndrome) or increased hepatic glucose production (as observed in type 2 diabetes) resulted from alterations in substrates oxidation/storage balance in the liver. Because AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor, it is important to gain understanding of the mechanism by which hepatic AMPK coordinates hepatic energy metabolism. AMPK has been implicated as a key regulator of physiological energy dynamics by limiting anabolic pathways (to prevent further ATP consumption) and by facilitating catabolic pathways (to increase ATP generation). Activation of hepatic AMPK leads to increased fatty acid oxidation and simultaneously inhibition of hepatic lipogenesis, cholesterol synthesis and glucose production. In addition to a short-term effect on specific enzymes, AMPK also modulates the transcription of genes involved in lipogenesis and mitochondrial biogenesis. The identification of AMPK targets in hepatic metabolism should be useful in developing treatments to reverse metabolic abnormalities of type 2 diabetes and the metabolic syndrome.
Leiden University Medical Center1, University of Toronto2, Paris Descartes University3, Université de Montréal4, University of Groningen5, University of Crete6, University of Lisbon7, University of Southampton8, Istanbul University9, Autonomous University of Madrid10, Ghent University11, University of Giessen12, University College Cork13, University of Copenhagen14, Universidade Federal de Santa Catarina15, University of Naples Federico II16, Menzies Research Institute17
TL;DR: In the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8, 751 rheumatologists from 17 countries participated in three separate rounds of discussions and Delphi votes as mentioned in this paper.
Abstract: Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.
TL;DR: This work compares conscious and nonconscious processing of briefly flashed words using a visual masking procedure while recording intracranial electroencephalogram (iEEG) in ten patients and argues that all of those measures provide distinct windows into the same distributed state of conscious processing.
Abstract: We compared conscious and nonconscious processing of briefly flashed words using a visual masking procedure while recording intracranial electroencephalogram (iEEG) in ten patients. Nonconscious processing of masked words was observed in multiple cortical areas, mostly within an early time window (<300 ms), accompanied by induced gamma-band activity, but without coherent long-distance neural activity, suggesting a quickly dissipating feedforward wave. In contrast, conscious processing of unmasked words was characterized by the convergence of four distinct neurophysiological markers: sustained voltage changes, particularly in prefrontal cortex, large increases in spectral power in the gamma band, increases in long-distance phase synchrony in the beta range, and increases in long-range Granger causality. We argue that all of those measures provide distinct windows into the same distributed state of conscious processing. These results have a direct impact on current theoretical discussions concerning the neural correlates of conscious access.
TL;DR: CX3CR1 deficiency selectively impairs the recruitment of blood Gr1+ monocytes in the spleen after transfer and during acute Listeria monocytogenes infection but does not affect the development of monocytes, cDCs, and PDCs.
Abstract: CX3CR1 expression is associated with the commitment of CSF-1R+ myeloid precursors to the macrophage/dendritic cell (DC) lineage. However, the relationship of the CSF-1R+ CX3CR1+ macrophage/DC precursor (MDP) with other DC precursors and the role of CX3CR1 in macrophage and DC development remain unclear. We show that MDPs give rise to conventional DCs (cDCs), plasmacytoid DCs (PDCs), and monocytes, including Gr1+ inflammatory monocytes that differentiate into TipDCs during infection. CX3CR1 deficiency selectively impairs the recruitment of blood Gr1+ monocytes in the spleen after transfer and during acute Listeria monocytogenes infection but does not affect the development of monocytes, cDCs, and PDCs.
TL;DR: There were noticeable clinical differences between HNF1α–inactivated HCA and IHCA; there was no increased risk of bleeding or HCC related to the number of HCAs; β‐catenin–activated HCAs are at higher risk of HCC.
TL;DR: The present knowledge concerning this subset of B cells and the arguments in favor of the proposition that humans have evolved for their MZ B cell compartment a separate B cell population that develops and diversifies its Ig receptor during ontogeny outside T-dependent or T-independent immune responses are reviewed.
Abstract: Human marginal zone (MZ) B cells are, in a sense, a new entity. Although they share many properties with their mouse counterpart, they also display striking differences, such as the capacity to recirculate and the presence of somatic mutations in their B cell receptor. These differences are the reason they are often not considered a separate, rodent-like B cell lineage, but rather are considered IgM memory B cells. We review here our present knowledge concerning this subset and the arguments in favor of the proposition that humans have evolved for their MZ B cell compartment a separate B cell population that develops and diversifies its Ig receptor during ontogeny outside T-dependent or T-independent immune responses.
TL;DR: It is shown that the introduction of delayed estimates affords significant improvement in numerical differentiation in noisy environment, and that the implementation in terms of a classical finite impulse response (FIR) digital filter is given.
Abstract: Numerical differentiation in noisy environment is revised through an algebraic approach. For each given order, an explicit formula yielding a pointwise derivative estimation is derived, using elementary differential algebraic operations. These expressions are composed of iterated integrals of the noisy observation signal. We show in particular that the introduction of delayed estimates affords significant improvement. An implementation in terms of a classical finite impulse response (FIR) digital filter is given. Several simulation results are presented.
TL;DR: Several lines of evidence for the existence of a 17q24 locus underlying Pierre Robin sequence are reported, including linkage analysis results, a clustering of translocation breakpoints, and a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer.
Abstract: Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.
TL;DR: The results show that RA is associated with a 60% increase in risk of CV death compared with general population, and targeting a reduction in CV mortality should still be considered as a major issue in RA.
Abstract: Objectives RA is known to be associated with a high cardiovascular (CV) risk. Longitudinal data suggest that RA disease course may have become milder over the past decades. Thus, we set out to estimate the magnitude of the overall increase in CV mortality associated with RA and to determine whether it has decreased over the past 50 years. Methods We performed a systematic review and a meta-analysis of literature in MEDLINE and EMBASE databases from January 1960 to November 2008. All cohort studies reporting CV mortality risk were included. We then calculated pooled standardized mortality ratios (SMRs) of CV mortality, and determined their evolution with time using meta-regression analysis. Results Seventeen studies were analysed, corresponding to a total of 91 916 patients. The overall pooled SMR was 1.6 (95% CI 1.5, 1.8; I(2) = 93%; P(het) 1990, five studies). Meta-regression analyses revealed neither any trend in SMR over time (P = 0.784) nor any relation with disease duration at the time of inclusion (P = 0.513). Conclusions Our results show that RA is associated with a 60% increase in risk of CV death compared with general population. Despite changes in RA course over the past decades, SMR for CV death has not changed. This suggests that targeting a reduction in CV mortality should still be considered as a major issue in RA.